Thesis defense: Amélie Joly

On September 23rd, Amélie Joly of the team of François Leulier will support his thesis entitled:

"Sex-dependent effects of chronic protein malnutrition on the physiology of juvenile mice "

Abstract:

Protein malnutrition still affects over 150 million children worldwide. It has long-lasting consequences on the organism, including stunted growth and metabolic dysfunctions. The etiology of malnutrition is complex, combining maternal and environmental risk factors. More recently, meta-analyses have suggested that biological sex could also be a risk factor, with boys being more likely to be malnourished than girls. Numerous rodent studies have demonstrated that growth and metabolism are biological processes differentially regulated by sex, but the sex-specific consequences of juvenile protein malnutrition remain unknown. Using a mouse model, we tested the hypothesis that the physiological response to juvenile protein malnutrition differs between males and females. To this end, we fed mice either a control diet or a low-protein diet for 5 weeks after weaning. At the end of the procedure, malnourished males were smaller and leaner than control males. In contrast, malnourished females showed minimal growth retardation. Furthermore, energy balance - including food efficiency, energy expenditure, glucose and lipid metabolism - is completely deregulated in response to malnutrition in males, but is little or not altered in females. However, the apparent adaptation of females to a low-protein diet is to the detriment of their sexual maturation. Indeed, malnourished females show disturbed puberty, detected by delayed vaginal opening, low uterine weight and irregular estrus cycles. In contrast, male sexual maturation is unaffected by malnutrition. Our data therefore suggest that juvenile mice allocate their energy resources differently in response to protein malnutrition depending on their sex, with males investing in sexual maturation and females in growth and metabolic homeostasis. What could be the mechanisms underlying these developmental trade-offs? The lack of protein in the diet is detected in particular in the liver via activation of the GCN2 (General control nonderepressible 2) kinase, which controls a vast transcriptional program. Hepatic transcriptional analysis has confirmed that the metabolic response to protein malnutrition is sexually dimorphic, revealing that males and females respond to malnutrition by regulating different metabolic pathways. Indeed, we detected a sex-dependent activation of GCN2 targets in malnourished mice. In particular, the hepatokine FGF21 (Fibroblast Growth Factor 21) is more strongly induced in males than in malnourished females. FGF21 is known to regulate the adaptation of numerous physiological processes (energy metabolism, growth, puberty...) to a lack of protein in the diet. This hormone could contribute to the sexually dimorphic phenotypes observed in response to juvenile protein malnutrition.